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The American Journal of Drug and Alcohol AbuseEncompassing All Addictive Disorders

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Treatment of opioid use disorder with ibogaine:detoxification and drug use outcomes

Thomas Kingsley Brown & Kenneth Alper

To cite this article: Thomas Kingsley Brown & Kenneth Alper (2017): Treatment of opioid usedisorder with ibogaine: detoxification and drug use outcomes, The American Journal of Drug andAlcohol Abuse, DOI: 10.1080/00952990.2017.1320802

To link to this article: http://dx.doi.org/10.1080/00952990.2017.1320802

© 2017 The Author(s). Published by Taylor &Francis

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Treatment of opioid use disorder with ibogaine: detoxification and drug useoutcomesThomas Kingsley Brown, PhDa and Kenneth Alper, MDb

aUniversity of California, San Diego, CA, USA; bDepartments of Psychiatry and Neurology, New York University School of Medicine, New York, NY, USA

ABSTRACTBackground: Ibogaine is a monoterpene indole alkaloid used in medical and nonmedical settings forthe treatment of opioid use disorder. Its mechanism of action is apparently novel. There are nopublished prospective studies of drug use outcomes with ibogaine. Objectives: To study outcomesfollowing opioid detoxification with ibogaine. Methods: In this observational study, 30 subjects withDSM-IV Opioid Dependence (25 males, 5 females) received a mean total dose of 1,540 ± 920 mgibogaine HCl. Subjects used oxycodone (n = 21; 70%) and/or heroin (n = 18; 60%) in respectiveamounts of 250 ± 180 mg/day and 1.3 ± 0.94 g/day, and averaged 3.1 ± 2.6 previous episodes oftreatment for opioid dependence. Detoxification and follow-up outcomes at 1, 3, 6, 9, and 12 monthswere evaluated utilizing the Subjective Opioid Withdrawal Scale (SOWS) and Addiction Severity IndexComposite (ASIC) scores, respectively. Results: SOWS scores decreased from 31.0 ± 11.6 pretreatmentto 14.0 ± 9.8 at 76.5 ± 30 hours posttreatment (t = 7.07, df = 26, p < 0.001). At 1-month posttreatmentfollow-up, 15 subjects (50%) reported no opioid use during the previous 30 days. ASIC Drug Use andLegal and Family/Social Status scores were improved relative to pretreatment baseline at all post-treatment time points (p < .001). Improvement in Drug Use scores was maximal at 1 month, andsubsequently sustained from 3 to 12months at levels that did not reach equivalence to the effect at 1month. Conclusion: Ibogaine was associated with substantive effects on opioid withdrawal symptomsand drug use in subjects for whomother treatments had been unsuccessful, andmay provide a usefulprototype for discovery and development of innovative pharmacotherapy of addiction.

ARTICLE HISTORYReceived 11 September 2016Revised 11 April 2017Accepted 16 April 2017

KEYWORDSIbogaine; alkaloid;18-methoxycoronaridine;noribogaine; heroin;oxycodone; prescriptionopioid; opioid use disorder

Introduction

Ibogaine, a monoterpene indole alkaloid that occurs inthe root bark of Tabernanthe iboga Baill., is used for thetreatment of substance use disorders (SUDs) (1,2). It hasbeen associated with controversy, and the medical andnonmedical settings of ibogaine use have been collectivelydesignated as a “vast uncontrolled experiment” (3), or“medical subculture” (1). Ibogaine has been classified asa hallucinogen and illegal in the US since 1967, and issimilarly scheduled in 9 of the 28 countries presently inthe European Union. It is unregulated, i.e., neither offi-cially approved nor illegal inmuch of the rest of the world.New Zealand, Brazil, and South Africa have classifiedibogaine as a pharmaceutical substance and restrict itsuse to licensed medical practitioners.

Ibogaine is used most frequently for detoxification fromopioids. A previous study on the known settings of ibogaineuse as of 2006 found that approximately 3,400 individualshad taken ibogaine, 68% of whom did so for the treatmentof a substance-related disorder, and 53% specifically for

opioid detoxification (1). A substantive effect of ibogainein opioid detoxification is reported in studies of 33 indivi-duals treated in nonmedical settings with single meandosages of 19.3 ± 6.9 mg/kg (4), and 32 individuals treatedin a medical setting with fixed dosages of 800 mg (5).Unpublished data include a series of 53 treatment episodesthat was presented to the National Institute on Drug Abuse(NIDA) and influenced NIDA’s decision to undertake anibogaine project from 1991 to 1995 (6), and an academicthesis on a Web-based survey of 21 individuals who hadused ibogaine (7). The subjects in these unpublished caseseries were predominantly opioid users, and ibogaineappeared to be effective in opioid detoxification, andabout one-third of subjects reported abstinence fromopioids for periods of 6 months or longer following treat-ment. A retrospective study on 75 subjects, a subset avail-able from a group of 195 individuals who have been treatedor cocaine dependence, almost none of whomused opioids,reported a median relapse-free interval of 5.5 months fol-lowing single doses of ibogaine of 7.5 to 20 mg/kg (8).Published follow-up regarding drug use outcomes beyond

CONTACT Kenneth Alper kenneth.alper@nyumc.org New York University School of Medicine, Departments of Psychiatry and Neurology, 560 FirstAvenue, New York, NY 10016, USA.Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/iada.

THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSEhttp://dx.doi.org/10.1080/00952990.2017.1320802

© 2017 The Author(s). Published by Taylor & FrancisThis is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or builtupon in any way.

detoxification in opioid use disorder (OUD) has been lim-ited to a small number of case reports (9–11).

Consistent with its apparent effect in opioid detoxifica-tion in humans, ibogaine administered intraperitoneally orintracerebrally to animals reduces naloxone- or naltrexone-precipitated opioid withdrawal signs, in rats (12–15), mice(16–19), and primates (20,21). Single dosages of ibogaineadministered to rodents diminish self-administration ofmultiple abused substances including morphine (22–25),heroin (26), cocaine (24,25,27–29), amphetamine (30), andalcohol (31), with normal responding for water. A notableaspect of these self-administration studies has been theobservation of a treatment effect of a duration of 48 to 72hours averaged for the entire sample, with sustained effectsfor longer time intervals in individual animals. Both ibo-gaine and its synthetic structural analog 18-methoxycoro-naridine (18-MC) diminish an experimental correlate ofdrug salience, the sensitized response of dopamine efflux inthe nucleus accumbens in response to morphine (32,33)and nicotine (34,35).

The mechanism of action of ibogaine is apparentlynovel, and unexplained by the receptor interactions ofmedications known to have clinical effects in opioid toler-ance or withdrawal (6,36,37). As a small molecule thatmodifies opioid withdrawal and drug self-administration,ibogaine may offer an interesting prototype for drug dis-covery and neurobiological investigation. Ibogaine, itsmajor metabolite noribogaine, and 18-MC do not act asorthosteric μ opioid receptor (MOR) agonists. Althoughibogaine, noribogaine, and 18-MC bind with low micro-molar affinity to the MOR, these compounds do not acti-vate G proteins assessed by the binding of [35S]GTPγS incells expressing the MOR (36), and the dosages of ibogaineused for detoxification in the setting of severe physicaldependence do not produce signs of overdose in opioid-naïve individuals (1).

Ibogaine potentiates morphine analgesia without pro-ducing analgesia when administered alone (16,38–43), asmight be expected of an allosteric MOR agonist.However ibogaine, noribogaine, and 18-MC do notpotentiate the activation of G proteins by morphine orDAMGO (36), indicating that these compounds do notact as allosteric MOR agonists. The reversal by ibogaineof analgesic tolerance to chronic morphine suggests thatibogaine may modify neuroadaptations associated withchronic exposure to opioids (39,43,44).

Ibogaine is an NMDA receptor antagonist (19,45), andNMDA antagonists such as memantine diminish signs ofopioid withdrawal in preclinical models and humans(46,47), however 18-MC lacks significant affinity for theNMDA receptor and is equally effective as ibogaine inanimal models of opioid withdrawal (12–15,37,48,49).Ibogaine has no significant affinity for the α2 receptor or

imidazoline I2 site (50,51), indicating that it does not actas an imidazoline α2 adrenergic receptor agonist such asclonidine (52).

The enhanced expression of glial-derived neuro-trophic factor (GDNF) has been proposed to accountfor ibogaine’s effect on drug self-administration (53).Ibogaine increases the GDNF expression in vivo and incultured cells, and 18-MC reportedly does not (54), butboth compounds are equally effective in animal modelsof drug self-administration (37). Ibogaine’s action as anallosteric antagonist of the α3β4 nicotinic acetylcholinereceptor (nAChR) is suggested to mediate its effect ondrug self-administration (55), but does not appear toreadily explain the prolonged effects that appear topersist beyond pharmacokinetic elimination (56).Ibogaine’s major metabolite, noribogaine (57,58) has alonger half-life than the parent compound, and hasbeen suggested to account for persistence of effects ondrug self-administration and withdrawal (59), althoughin the animal model the effect of ibogaine in reducingdrug self-administration appears to persist beyond theelimination of ibogaine and noribogaine from serum orbrain tissue (56).

There are no published prospective studies of ibogainein the treatment of OUD reporting on drug use outcomessubsequent to detoxification. This study reports on out-comes up to one year following opioid detoxification withibogaine.

Methods

Treatment setting, inclusion and exclusion criteria,and subject enrollment

The Human Research Review Committee at theCalifornia Institute of Integral Studies approved thisobservational study. By definition, an observationalstudy assesses dependent variables, in this case detoxifica-tion and drug use outcomes, without modifying the inde-pendent variable, in this case the parameters of treatment,and the investigators had no role in administering ibo-gaine or clinical management. This study is naturalisticwith respect to its focus on treatment as usual in a repre-sentative setting of two private clinics that provided treat-ment with ibogaine on a fee-for-service basis, locatedrespectively in Ensenada (25 subjects), and Playas deTijuana (5 subjects) in Baja California, Mexico.Treatment consisted of administration of ibogaine fol-lowed by a clinic stay of 3 to 6 days.

The study sample consisted of 30 individuals whosought treatment with ibogaine for detoxification fromopioids. All of the subjects met criteria for DSM-IVOpioid Dependence with Physiological Dependence on

2 T. K. BROWN AND K. ALPER

opioids (60). Individuals were excluded from the study ifthey took ibogaine for any purpose other than the treat-ment of OUD, if they had a history of prior treatmentwith ibogaine, or if they appeared to have personal, health,situational, social or other problems which in the view ofthe investigator would prevent them from being able tofully comply with the requirements of this study. Asadmission criteria, subjects were required to have a reli-able method of communication by which the researcherscould contact them during the study follow-up period andto provide the name and contact information of at leastone other individual such as a therapist, counselor, par-ent, spouse or close friend, to communicate with theresearch team and provide corroboration regarding thesubject’s drug use.

During the enrollment period, 30 subjects signed theInformation and Consent Form and were enrolled intothe study. An additional nine individuals were notenrolled because they had received ibogaine before theycould be asked to participate in the study, and 4 declinedto participate. Participants were given $10 in the form ofa gift certificate for each follow-up phone interview theycompleted after leaving the clinic.

Study sample

Table 1 summarizes demographic, drug use, and treat-ment history characteristics of the study sample. At thetime of enrollment in the study, the drugs most com-monly cited as the most problematic were heroin (n = 14),and prescription analgesic opioids (n = 10), mostly oxy-codone. Subjects were heavy, and relatively selective usersof opioids, averaging 29.0 ± 3.2 days of opioid use in theprevious 30 days. Eighteen subjects (60%) reported nostimulant use and 18 (60%) reported no alcohol use in theprevious 30 days, and only 3 subjects reported five ormore drinking occasions of at least five drinks in theprevious 30 days. At pretreatment baseline (N = 30),Drug Use was the highest and Alcohol Use was the lowestof all of the ASIC scores (see Table 2).

Subjects had been regularly using at least one opioidsubstance for an average of 5.2 ± 3.0 consecutive yearsbefore presenting for treatment. On days the subjectsused heroin, they averaged 1.3 ± 0.94 g/day, the major-ity by the intravenous route. Among users of oxyco-done, the mean daily amount of oxycodone used was250 ± 180 mg/day. Twenty-nine of the 30 subjects(97%) had previously received treatment for SUD, andthe study sample averaged 3.1 ± 2.6 prior treatmentepisodes, most commonly methadone or buprenor-phine maintenance or residential treatment.

Treatment

Prior to the administration of ibogaine and subsequent toarrival at the clinic, subjects were stabilized on a shortacting opioid,most often oxycodone, for two to three daysin a range of 90 mg to 270 mg per day divided into threedoses. Subjects on long-acting opioids had beeninstructed to change over to short acting opioids for atleast two weeks prior to their treatment. An average totaldose of 1,540 ± 920 mg ibogaine HCl, 94% purity bycertificate of analysis was administered to each subjectas described below. Five of those subjects additionallyreceived a crude extract of T. iboga root bark (meandose 1610 ± 1650 mg). Crude “total alkaloid” extractshave an estimated total alkaloid content between 15%and 50%, about 25% to 50% of which might be expectedto be ibogaine (1,61). No opioids were administered sub-sequent to the initiation of treatment with ibogaine, andsubjects did not receive any additional ancillarymedications.

The treatment was initiated with a “test” dose of ibo-gaine of 3 mg/kg, typically administered in the morningafter subjects had abstained from opioid use overnight.The test dose was given when subjects had begun toexhibit three or more initial signs of withdrawal, such asrestlessness, sweating, yawning or watery eyes. In theexperience of ibogaine treatment providers, the test dosetypically has some effect of reducing withdrawal signs,and they view the response to the test dose as providingsome indication of the degree of physical dependence onopioids. A larger, “flood” ibogaine dose, typically fourtimes the test dose is given approximately 2 to 12 hoursafter the test dose. The flood dose was sometimes followedby an additional “booster” dose of ibogaine of 3 to 5 mg/kg, at an interval following the flood dose commonly inthe range of 1 to 16 hr. Providers administered boosterdosages to alleviate residual or re-emergent withdrawalsymptoms, or at the election of the patient to increase theintensity of the psychoactive experience.

A set of clinical guidelines for detoxification fromopioids with ibogaine has been published online by agroup of physician and lay ibogaine treatment providers(62) and is representative of the approach by the providersof treatment in this study. Briefly, pre-treatment evalua-tion included medical history, EKG, and electrolyte andliver function tests. Monitoring throughout the treatmentincluded continuous pulse oximetry and three-lead EKG,andmonitoring of blood pressure. Intravenous access wasmaintained during the treatment, with a medical profes-sional (MD, nurse, or paramedic) certified in AdvancedCardiac Life Support (ACLS) present for at least the first24 hours of the treatment.

THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 3

Assessment and rating

The baseline pretreatment interview was conducted afterthe participant’s arrival at the clinic, one to three days priorto the administration of ibogaine. The first author (T.B.)conducted the follow-up interviews with subjects and theirsignificant others, either in-person at the clinic or by tele-phone. Subjects were followed up at intervals of 1, 3, 6, 9,and 12months following treatment with ibogaine. Amem-ber of the research team also attempted to contact by phonea corroborating person identified by the study participantto independently verify information regarding the partici-pant’s substance use from the time of baseline assessmentthroughout the 12-month follow-up period.

Subjects were evaluated using the Addiction SeverityIndex (ASI), Lite version (63) at pretreatment baselineand at follow-up intervals of 1, 3, 6, 9, and 12 monthsafter treatment with ibogaine. TheASI has seven compositemeasures with distinct item content entitled Drug Use,Alcohol Use, and Family/Social, Employment, Legal,Medical, and Psychiatric Status (64). Each ASI Composite

(ASIC) score is a sum of values of ASI items, scaled var-iously as the number of days in the last 30 days, logtransformation, binary values, or as continuous ratings ofseverity. ASIC item values are normalized relative to theirmaximal possible values, weighted equally and summed.The item sum totals divided by the number of items yieldsthe ASIC score with a value in the range of 0 to 1.0. HigherASIC scores indicate greater problem severity.

Detoxification outcomes were assessed with the 16-itemSubjective Opioid Withdrawal Scale (SOWS) (65), whichconsists of 16 questions regarding withdrawal symptomson a zero through the four-point scale. The baseline SOWSwas administered within one hour prior to the test dose.The time intervals between test, flood and possible boosterdosages were at the election of the provider and non-uni-form across subjects. The follow-up SOWS was adminis-tered when the provider viewed the treatment ascompleted, with no need for further dosing, with the sub-ject exhibiting no withdrawal signs, ambulating and com-municating normally, and eating.

Table 1. Demographic and drug use characteristics and prior treatment history of the study sample.DemographicsN 30Gender 25 male, 5 femaleAge 29.0 ± 9.0 yearsEthnicity 27 Caucasian, 1 Hispanic, 2 otherYears of education 13.6 ± 1.7Usual employment, past 3 years Employed full-time 13 (43%); part-time

8 (27%); unemployed 5 (17%); student 3(10%); retired /disability 1 (3%)

Any illegal source of income in past 30 days 13 (43%)Substance useSubstance self-reported as most problematic Heroin (14), prescription opioid

analgesics (10), buprenorphine (3),methadone (2), opium (1)

Mean number different opioid substances used 2.2 ± 1.1Mean duration of opioid use 5.2 ± 3.0 yearsPredominant route of heroin self-administration Intravenous (12), smoking (5), intranasal (1)Substances Number using (%) Days used in previous 30 days Mean daily amount when usingAll opioid substances 30 (100%) 29.0 ± 3.2 –All prescription opioid analgesics 23 (77%) 21.4 ± 9.2 –Oxycodone 21 (70%) 20.8 ± 9.9 250 ± 180 mgHeroin 18 (60%) 22.7 ± 10.1 1.3 ± 0.94 gramsMethadone (maintenance) 5 (17%) 20.2 ± 6.8 110 ± 60 mgMethadone (other source) 4 (13%) 3.3 ± 1.5 30 ± 16 mgBuprenorphine (maintenance) 6 (20%) 13.3 ± 10.4 5.8 ± 1.7 mgBuprenorphine (other source) 1 (3%) 8 2 mgOpium 1 (3%) 30 1.5 gCannabis 20 (67%) 17.6 ± 12.3 1.7 ± 3.5 gramsBenzodiazepines 14 (47%) 14.7 ± 11.2 –Alcohol 12 (40%) 10.3 ± 8.4 5.4 ± 4.6 drinksCocaine 10 (33%) 12.9 ± 10.4 1.3 ± 1.1 gramsMethamphetamine 3 (10%) 12.0 ± 9.2 200 ± 250 mgClassical hallucinogens 3 (10%) 3.0 ± 2.6 –>1 substance per day 29 (97%) 20.6 ± 8.4 –Prior treatment historyMean number of previous treatment episodes for opioid dependence 3.1 ± 2.6Prior opioid treatment episodes, type Number of subjects (%)Any prior treatment for opioid dependence 29 (97%)Buprenorphine or methadone maintenance 16 (53%)Detoxification only 10 (33%)Residential treatment 16 (53%)12-step or other group therapy 7 (23%)Treatment for alcohol dependence 3 (10%)Inpatient psychiatric hospitalization 9 (30%)

4 T. K. BROWN AND K. ALPER

Statistical tests

The effect of ibogaine in opioid detoxification was eval-uated with paired t-tests comparing pre- versus posttreat-ment SOWS scores. Posttreatment follow-up ASIC scoreswere compared using paired t-tests and noninferioritytests. Statistical analysis was performed using SAS® soft-ware Version 9.4 of the SAS System for Windows 10.

Paired t-tests were used to compare ASIC scores at 1, 3,6, 9 and 12 months to their pretreatment baseline. Anadditional question posed to the ASI data was whether atreatment effect observed at 1 month was sustained atsubsequent 3-, 6-, 9-, and 12-month time points. Onemonth was selected on the basis of prior observation as aposttreatment time interval at which an ibogaine treatmenteffect is particularly evident (1). This question wasaddressed with noninferiority tests (66,67) on the 20subjects available for follow-up at 1 month. The nullhypothesis of the noninferiority test is that the posttreat-ment 3-, 6-, 9-, and 12-month ASIC scores are greater(worse) than their 1-month posttreatment values by amargin of ≥0.1 ASIC point. Rejection of the null hypothesison the basis of a low p-value indicates that relative to its 1-month value, the ASIC score at the later time point had notincreased by a margin of ≥0.1 point, and was noninferior,i.e., not worse, suggesting a sustained treatment effect thatis at least equivalent, or better relative to that seen at 1month. Conversely, nonsignificant noninferiority indicates

that the effect at the later time point does not reach equiva-lence to the effect evident at 1 month.

As a conservative adjustment for missing follow-updata, the p-values of the statistical tests on ASIC scoreswere calculated setting missing posttreatment valuesequal to their baseline pretreatment value. Pairedt-tests comparing posttreatment values to their pre-treatment baseline were performed utilizing the totalstudy N = 30 subjects, setting the missing values ofsubjects unavailable at the 1-, 3-, 6-, 9-, and 12-monthtime points to their pretreatment baseline values. Thenoninferiority tests used 1-month values as the refer-ence comparison, so these tests were performed on onlythose n = 20 subjects that were available for follow-upat 1 month, with missing subsequent 3-, 6-, 9-, and12-month values set to their pretreatment baseline values.

Results

Sows

The SOWS score for the entire study sample (a pre- andposttreatment SOWS was returned on 27 subjects)decreased from pretreatment baseline 31.0 ± 11.6 to 14.0± 9.8 following ibogaine treatment, a mean reduction of17.0 ± 12.5 points (t = 7.07, df = 26, p < .001). The meantime interval between the baseline and second SOWS was76.5 ± 30 hrs.

Table 2. ASIC scores at pretreatment baseline and 1, 3, 6, 9, and 12 months, and opioid free days: Paired t-tests were used tocompare ASIC scores at 1, 3, 6, 9, and 12 months posttreatment to their baseline pretreatment values (N = 30; significance level ofp-values indicated by †). Noninferiority tests were used to compare ASIC scores at 3, 6, 9, and 12 months posttreatment to their 1-month posttreatment values (n = 20; significance level of p-values indicated by *). The means and standard deviations areunadjusted and computed on the subjects (n) available at the respective time point. The p-values are adjusted for missingfollow-up data by performing the respective statistical tests with missing values set equal to their baseline pretreatment value asdescribed in Methods. Opioid-free days in the previous 30 days are shown in the lower part of the Table.

Pretreatment One month 3 months 6 months 9 months 12 months

n 30 20 19 14 17 14

ASIC ScoresDrug Use 0.40 ± 0.08 0.11 ± 0.09††† 0.15 ± 0.13††† 0.12 ± 0.09††† 0.13 ± 0.13††† 0.17 ± 0.10†††

Alcohol Use 0.08 ± 0.18 0.09 ± 0.13 0.07 ± 0.11*** 0.16 ± 0.16* 0.12 ± 0.13* 0.16 ± 0.24Family/Social Status 0.24 ± 0.16 0.07 ± 0.13††† 0.06 ± 0.13†††** 0.08 ± 0.15††* 0.03 ± 0.09†††* 0.04 ± 0.07†††

Employment Status 0.34 ± 0.26 0.44 ± 0.28†† 0.33 ± 0.27** 0.26 ± 0.22*** 0.37 ± 0.29*** 0.25 ± 0.19***

Legal Status 0.22 ± 0.24 0.10 ± 0.18†† 0.04 ± 0.09††** 0.14 ± 0.14†* 0.05 ± 0.10†** 0.10 ± 0.17††*

Medical Status 0.19 ± 0.31 0.26 ± 0.28 0.27 ± 0.34* 0.25 ± 0.28** 0.15 ± 0.31** 0.26 ± 0.35**

Psychiatric Status 0.27 ± 0.18 0.18 ± 0.22 0.17 ± 0.20†* 0.16 ± 0.23††* 0.14 ± 0.20 0.23 ± 0.20Opioid-free days in the previous 30 daysAmong subjects availablefor follow up

1.0 ± 3.3 27.7 ± 5.7 22.5 ± 11.2 20.2 ± 13.5 20.6 ± 13.4 17.3 ± 14.0

Among all subjects(N=30), missing valuesset to pretreatmentbaseline

1.0 ± 3.3 18.9 ± 13.6 14.9 ± 13.7 9.9 ± 13.6 11.7 ± 14.4 8.8 ± 12.7

Number of subjectsreporting no opioiduse in previous 30days (%N)

0 15 (50%) 10 (33%) 6 (20%) 11 (37%) 7 (23%)

Paired t-tests (†): †p < .05; ††p < .01; †††p < .001.Noninferiority tests (*): *p < .05; **p < .01; ***p < .001.

THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 5

The original study of the development and validation ofthe 16-item SOWS by Handelsman et al. (65) found thatthat the effect of methadone on SOWS scores was smallerin opioid-dependent subjects with comorbid abuse of othersubstances (alcohol, stimulants, or sedative/hypnotics)relative to those without comorbid substance abuse (65).Accordingly, we compared pre- versus posttreatmentchange in SOWS scores in subjects with (n = 11), andwithout (n = 16) comorbid substance use, defined as 5 ormore drinking occasions of at least 5 drinks, any stimulantuse, or more than 5 days of use of benzodiazepines in theprevious 30 days. No significant difference was found,SOWS scores decreased by 16.8 ± 12.4 points in thegroup with comorbid substance use, versus 17.2 ± 12.7points in the group without (t = 0.09, df = 20.7, p = .928).

Tests of difference on ASIC scores relative tobaseline at 3-, 6-, 9-, and 12-month follow-up

Table 2 summarizes the results of paired t-tests ofdifference on ASIC scores comparing 1-, 3-, 6-, 9-,and 12-month values to their pretreatment baseline.In the Table, p-values are adjusted for missing data asdescribed in Methods, and the ASIC scores areunadjusted. Significantly decreased ASIC scores, indi-cating improvement relative to pretreatment baselinewere evident at all posttreatment time points for DrugUse (p < .001 at 1, 3, 6, 9, and 12 months), Family/Social Status (p < .001 at 1, 3, 9 and 12 months; p < .01at 6 months), and Legal Status (p < .01 at 1, 3, and 12months; p < .05 at 6 and 9 months).

Alcohol Use and Medical Status scores did not differsignificantly from baseline at any time point. The apparentlack of a clear trend regarding the Alcohol Use score acrossthe posttreatment follow-up interval may reflect the rela-tively low use of alcohol in the study sample. A decrease inPsychiatric Status scores from baseline at 1 month

approached significance (p = .053, data not shown inTable), and scores were lower than their pretreatmentbaseline at 3 months (p < .05) and 6 months (p < .01).The Employment Status score was significantly increasedrelative to pretreatment baseline only at 1 month (p < .01),without significant differences at other time points, possi-bly explained by the interruption of employment in orderto participate in treatment.

Tests of noninferiority on ASIC scores relative to 1month over the subsequent posttreatment intervalof 3 to 12 months

Table 2 includes noninferiority tests of ASIC scores at 3-,6-, 9-, and 12-month posttreatment follow-up comparedto 1-month posttreatment, with p-values adjusted formissing subjects as described in Methods. The noninfer-iority tests were significant for Family/Social (p < .01 at 3months; p < .01 at 6 and 9 months) and Legal Statusscores (p < .01 at 3 and 9 months; p < .05 at 6 and 12months) indicating that improvement in these measuresat the 1-month posttreatment interval was sustained atthese subsequent time points.

The noninferiority results on Drug Use scores adjustedfor missing data were not significant at any time point(Table 2). In contrast, without the adjustment for missingdata, the noninferiority results on Drug Use scores aresignificant at p < .001 at all posttreatment time points(data not shown). Figure 1 plots individual trajectories onthe Drug Use score across the duration of the study, andappears to indicate an effect at 1 month that persists up to12 months in a subset of individual subjects. The differ-ential significance of the noninferiority test results utiliz-ing adjusted in contrast to unadjusted Drug Use scoreslikewise suggests a subset of responders for whom atreatment effect is sustained across the 12-month follow-up interval, although the group noninferiority result

Figure 1. Individual trajectories of the ASIC Drug Use score in all subjects available at one or more follow-up time points subsequentto treatment (n = 26).

6 T. K. BROWN AND K. ALPER

becomes nonsignificant under the conservative assump-tion that all missing subjects have relapsed to their base-line. For the entire sample of subjects, taken together withthe results of the paired t-tests on ASIC scores that com-pare subsequent time points with pretreatment baseline,the noninferiority results suggest sustained reduction inDrugUse relative to pretreatment baseline across the 3- to12-month posttreatment interval that does not reachequivalence to the effect evident at 1 month.

Psychiatric Status scores were significantly noninfer-ior (p < .05), at 3 and 6 months, indicating that themarginal 1-month improvement relative to baselinewas sustained at these subsequent time points. AlcoholUse and Medical Status scores yielded some significantresults on noninferiority tests, however neither scorediffered from baseline as indicated by the paired t-tests(Table 2), here the significant noninferiority results areconsistent with the apparent stability of these scoresacross the pre- and posttreatment time interval.Similarly, apart from the transient elevation at 1 monthnoted above, Employment Status scores were unchangedfrom baseline at all other time points, with the signifi-cant noninferiority results consistent with the relativestability of this score at time points other than 1-monthposttreatment.

Relationship of baseline characteristics tosubsequent outcome

A subset of 12 subjects had favorable outcomes, defined asretention at 9 or 12 months with ≥75% reductions of theDrug Use score relative to pretreatment baseline. This sub-set of 12 subjects with favorable outcomes did not differsignificantly from the remaining subjects (n = 18) withregard to any of the demographic features in Table 1. Nodifferencewas foundbetween these two groupswith respectto their rates of use of non-opioid substances, or opioidsother than methadone (see below), although there was amarginally higher rate of benzodiazepine use in the groupwith less favorable outcomes (Fisher’s Exact p = .072). Thetwo groups did not differ regarding whether the substancethey identified as most problematic was heroin (Fisher’sExact p = .457) or prescription opioid analgesics (Fisher’sExact p = .622), or whether they reported the intravenousroute as the predominant route of heroin self-administra-tion (Fisher’s Exact p = .709).

Exposure to methadone, defined as any use of metha-done in the previous 30 days or a prior history of metha-done maintenance treatment, was associated with lessfavorable outcome (Fisher’s Exact p = .002). In contrast,exposure to buprenorphine did not differ between the twogroups (Fisher’s Exact p > .999). The subjects with lessfavorable outcomes averaged 3.8 ± 2.9 prior treatment

episodes versus 2.0 ± 1.6 in the favorable outcome group(t = 2.16, df = 27.3, p = .041). Subjects with histories ofmethadone treatment (n = 13) had a mean of 4.5 ± 3.1prior treatment episodes, compared to 2.0 ± 1.5 in thesubjects (n = 17) without a history of methadone treat-ment (t = 2.66, df = 16.4, p = .017). The dataset did notpermit an analysis of mediation of outcome by metha-done exposure per se versus the number of prior treat-ment episodes.

Subjects receiving other SUD treatment duringfollow-up

A total of 9 subjects received additional treatment duringthe 12 months following opioid detoxification with ibo-gaine, with a total of 10 treatment episodes: drug-freeresidential (n = 4; mean 2.3 ± 1.1 months, range 0.5 to3.1 months), opioid agonist maintenance (n = 3; mean 2.3± 2.2 months, range 1.0 to 4.8 months), or an additionalsubsequent ibogaine treatment (n = 3). Two of the 12subjects in the favorable outcome group received addi-tional treatment, compared to 7 of the 18 remainingsubjects (Fisher’s Exact p = .249).

In the statistical analyses subjects in residential treat-ment were assumed to be missing and their missing ASICscore values set to pretreatment values, and these subjectswere not included in the subset who reported no opioid usein the previous 30 days. Previous 30-day use of methadoneor buprenorphine in the context of maintenance or fromanother source was regarded as opioid use and assessedusing the ASI as with other subjects and time points.

Adverse events

No clinically significant cardiovascular or other medicalevents occurred in this study.

Discussion

This observational study reports on follow-up data sub-sequent to detoxification with ibogaine of 30 individualswith OUD. The data appear to indicate treatment effectsin detoxification, and on the use of opioids and othersubstance use-related outcomes at 1 month, sustained toa variable extent over the subsequent posttreatmentinterval of up to 12 months.

The reduction in SOWS scores in this study is consis-tent with prior case series (4,5), and the status of opioiddetoxification as the purpose for which ibogaine is mostcommonly used (1). The clinical effect of ibogaine onopioid withdrawal symptoms appears of a comparableorder of magnitude to that of methadone in the studyby Handelsman et al. (65), in which subjects withdrawing

THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 7

from opioids were administered the SOWS at pretreat-ment baseline and following two days of methadonestabilization. In that study, the SOWS decreased by amean of 18.7 points (from 24.3 to 5.6) in subjects whoused opioid exclusively, and 8.7 points (from 23.1 to 14.4)in subjects who additionally abused other, non-opioidsubstances. In the present study, the mean SOWSdecrease following the administration of ibogaine was 17points (from 31 to 14), without a significant effect relatedto the use of non-opioid substances.

The effect of ibogaine on drug use at 1 month appearssubstantive relative to reported outcomes followingopioid detoxification. In this study 15 (50%) and 10(33%) of subjects reported no opioid use during theprevious 30 days at 1 and 3 months respectively(Table 2). By comparison, a large recent study reportedan 8.6% rate of treatment success, defined as self-reportof ≤4 days of opioid use in the previous 30 days, at 8weeks subsequent to tapering and discontinuing bupre-norphine with no subsequent pharmacotherapy (68).Recent systematic reviews on follow-up of opioid detox-ification without subsequent maintenance treatmentreport rates of abstaining from illicit opioid use of 18%at 4 weeks following detoxification with buprenorphine(69), and 26% at 6 weeks following detoxification withmethadone (70).

Group statistics indicated Drug Use scores wereimproved relative to pretreatment baseline at all posttreat-ment time points, although the noninferiority tests sug-gest that this improvement was sustained over thesubsequent 3 to 12 months at levels that did not reachequivalence to the effect observed at 1 month. Treatmentresponses in clinical populations occur in subsets of indi-viduals, and not as a uniformly equal mean effect acrossall subjects. Figure 1 suggests treatment effects extendingup to 12 months in a subset of individuals, evident astrajectories characterized by large Drug Use scoredecreases from baseline to 1 month that are sustained atsubsequent time points.

The subset of 12 subjects with favorable outcomesaveraged 2.0 ± 1.6 prior treatment episodes for OUD,indicating that ibogaine may have provided distinctivebenefit for individuals with histories of previouslyunsuccessful treatment. There was a higher prevalenceof a history of methadone maintenance and a greaternumber of prior treatments in the group with lessfavorable outcomes. It is not clear whether the effectof exposure to methadone on outcome was mediated bya general association of exposure to methadone as acorrelate of a history of more treatment episodes, or apossible pharmacologically mediated effect of exposureto methadone per se, such as the development of rela-tively more severe physiological dependence.

Although no adverse cardiovascular events wereobserved in this study, ibogaine has been associatedwith fatalities, the most common proximal cause ofwhich appears to be cardiac arrhythmia (61,71).Ibogaine has been associated with polymorphic ventri-cular tachycardia (PVT) including torsade de pointes(TdP), as well as bradycardia, which further potentiatesthe risk of PVT (72). Both ibogaine and noribogainecause blockade of the voltage-gated cardiac potassiumchannel encoded by the human ether-a-go-go-relatedgene (hERG) (73), which is the most common cause ofdrug-induced TdP (72). 18-MC, which shares with ibo-gaine the same ibogamine structural skeleton thatdefines the iboga class of monoterpene indole alkaloids,produces substantially less hERG blockade than ibogaineor noribogaine (73), and has not produced bradycardiain the animal model (74). This suggests that safer com-pounds can be designed utilizing systematic substitu-tions on the iboga alkaloid scaffold.

Qualitative perspective

Some themes are recurrent in comments made in inter-views and email correspondence by study participants, whoappear to have viewed the subjective experience with ibo-gaine as psychologically salient. Distinctive features of thesubjective experience mediated by ibogaine include whathas been termed “the slide show”, a panoramic, rapidreadout of long-term visual memory, and equanimityregarding thematerial retrieved (75,76). Some practitionerswho have used classical hallucinogens to assist psychother-apy have utilized ibogaine (1,77,78). Family/Social was themost improved ASIC factor apart from Drug Use, inapparent consonance with the themes of “one hearted-ness”, and “binding” of the individual to family and ances-tors in Bwiti, the African context of sacramental use of T.iboga (76,79). Lotsof has suggested that effects on drug useand interpersonal functioning at later intervals after takingibogaine may correspond to processing and behavioralintegration of a psychodynamically salient psychoactiveexperience (11,75).

One theme among study participants was the attribu-tion of insight and meaning to the content of the psy-choactive state produced by ibogaine. One subject wrote,“I saw my family from young to older and how everythinghas been and how I affected them.” and, “When I closed myeyes most of the time I had visions from my past. . . Aprofound sense of love for my family and their love for meand an intense, almost piercing agony as I was over-whelmed with the remorse and the waste and loss, feelingempathy with my family over all their hopes for me dashedby my relentless pursuit of drugs. . . I kept seeing clips – realmemories, of high-school girlfriends and playingmusic with

8 T. K. BROWN AND K. ALPER

friends – but then also clips of the present day in analternate reality where I hadn’t squandered so much loveor compassion that had been offered to me.”

Another theme was the characterization of an intervalof diminished posttreatment drug craving as a window ofopportunity for personal change, evident in commentssuch as, “. . .you could safely say that iboga will give anopiate addict several months to a half a year of freedomfrom cravings and an expanded awareness. This gives theuser a period of time in which to get his/her life togetherand learn to face things straightforwardly, directly andhonestly. Iboga will not do the work for you. However, itwill help you do your own work.”

Limitations of this study

This is a study on an unusual pharmacotherapy in achallenging setting for systematic controlled clinicalinvestigation. There were a limited number of subjectsand substantial attrition over time. This study lacked acontrol group and compared individuals to their baseline.This study relied on self-report without laboratory verifi-cation, with the ASIC Drug Use score as the primarymeasure of substance use outcome. Adequately poweredrandomized controlled clinical studies will be needed todevelop ibogaine or its structural derivatives.

Laboratory verification of self-reports are a necessaryfeature in future clinical research to prevent biasing thedata due to underreporting of drug use. Nonetheless,self-reporting in clinical research on SUDs is oftenaccurate (80), particularly when there are no negativeconsequences to the subject for reporting use. Thestudy inclusion criterion requiring a corroborativesource may have provided additional reliability.

The mean time interval between baseline and secondSOWS for the entire sample was 76.5 hours, raising apotential concern that in this time frame even an inactiveagent might yield falsely positive results on the basis of theeventual resolution of symptoms with unassisted opioidwithdrawal. This view would take as evidence for an effectin detoxification the resolution of withdrawal symptoma-tology within the time window of expected peak sympto-matic severity in unassisted opioid withdrawal. Publishedestimates of the time interval from last use to peak with-drawal symptom severity in unassisted withdrawal fromheroin are commonly in a range with a lower bound ofapproximately 48 hours (81–83), and an upper bound at 72hours (84,85), or even as long as four days (86,87). Theexpression of the opioid withdrawal syndrome may beprolonged with severe degrees of physiological dependence(82), which may be relevant here in view of high dosages ofheroin and oxycodone used by this study population(Table 1).

The subjects in this study had substantial rates ofprevious 30-day use of buprenorphine (23%) or metha-done (30%) (Table 1), and 15 subjects (50%) had usedat least one of these long-acting opioids in the previous30 days prior to ibogaine treatment. Withdrawal asso-ciated with long-acting opioids evolves and persistsover a more extended time interval compared to shortacting opioids (88–90), which may also have increasedthe time interval required for detoxification in thissample. Subjects on long-acting opioids had beeninstructed to switch to short acting opioids prior totreatment, but likely varied significantly regardingtheir success in doing so.

Another factor that may have prolonged the treat-ment is the test-flood-booster opioid detoxificationprotocol, which utilizes the response to the test doseas a probe to estimate the severity of dependence (62).Subjects in the present study were using amounts ofheroin and methadone that are twice as large as thoseused by subjects in earlier published series of detoxifi-cation treatments in the US in the 1960s and theNetherlands in the late 1980s (4,91), and heroin of thepresent day is of substantially greater purity and lowercost (92). However, the providers in this study utilizedtotal dosages of ibogaine that are very similar to thoseused in prior treatments (4), suggesting a dose ceiling.There is a relatively greater awareness of medical riskamong contemporary treatment providers (1,61,62)compared to the previous era of the initial ibogainetreatments (4). The test-flood-booster ibogaine dosageapproach utilized by the providers in this observationalstudy appears to be an adaptation intended towardmaximizing efficiency in the face of severe levels ofphysiological dependence, and contrasts with an earlierera in which opioid detoxification treatments with ibo-gaine proceeded more rapidly, with nearly all of thetotal ibogaine dosage administered at once (4).

The qualitative descriptions and comments from thesubjects in this study suggest tolerability as another lineof clinical evidence for a treatment effect of ibogaine indetoxification. The null hypothesis that ibogaine is ineffec-tive in alleviating withdrawal would equate its tolerabilityto that of unassisted withdrawal without any ancillarymedications for two to five days in individuals with a onegram/day heroin or 200 mg/day oxycodone habit. In viewof the lack of a significant placebo effect in opioid detox-ification (70,93,94), attributions regarding the effectivenessof ibogaine in the null scenario would be very low to say theleast, which did not occur in the present study. Amongsubjects who spontaneously mentioned withdrawal symp-toms when asked to provide descriptions of their ibogaineexperience, ibogaine was consistently attributed with alle-viating withdrawal.

THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 9

Conclusion

Within the limitations of an uncontrolled, observationalstudy ibogaine appeared to have a substantive treatmenteffect in opioid detoxification, and group statistics andindividual trajectories appear to indicate an effect of redu-cing drug use at 1 month, which was sustained up to 12months in a subgroup of subjects. Ibogaine appears to havehad a clinical effect in some subjects with histories of failureof other treatments for OUD. The iboga alkaloid structuralskeleton may be accurately regarded as a “privileged scaf-fold”, a structure of pharmacological significance on whichsystematic substitutions modulate therapeutic and toxiceffects (95,96).With an unknown and likely novel mechan-ism of action, and a structure that evidently accommodatesrational drug design, ibogaine may provide an interestingprototype for discovery and development of fundamentallyinnovative pharmacotherapy.

Acknowledgments

The Multidisciplinary Association for Psychedelic Studies(MAPS) supported this study. We thank the following indi-viduals for their effort in this project: Jeff Israel, ClareWilkins, Peter Flom, Ph.D., Julie Denenberg, M.A., KristinGorenflo, I.M.F.T., Mayra A. Gomez, Valerie MojeikoSonstroem, and Meg Jordan, Ph.D., R.N.

Declaration of interest

The authors report no conflicts of interest and have nofinancial interests to disclose.

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